Meniere's disease, a disorder of the inner ear, afflicts around 0.1-0.5% of the adult population. The disease is characterized by vertigo, hearing loss and tinnitus, and usually begins in the middle life, although it may manifest itself even at lower age. The disease occurs in both sexes at about the same rate. It typically occurs in episodes of marked vertigo, hearing loss and tinnitus, lasting for hours up to a few days, but also during the intermittent time periods the patients may suffer from tinnitus and hearing loss. Usually Meniere's disease is unilateral, but with time both ears may become involved, and an estimated 12 percent have bilateral disease.
Although the disease tends to be episodic with severe vertigo, nausea and hearing loss and subsequent remissions, with time patients usually suffer from general hearing loss and tinnitus. The remissions may last from a day to several years, but most commonly they last for a few weeks to months. Not uncommonly speech perception is reduced during the attacks. Complete deafness in the affected ear has been reported to occur at a rate of about 10 percent. The individual symptoms of Meniere's disease may vary greatly between patients as may the duration of the remissions, but the disease typically is chronic lasting the whole remaining life from its onset. The disease may impair the working ability and social life of the patients leading to psychological and mental disturbances, and in severe cases patients have even committed suicide because of the disease.
The pathophysiology of Meniere's disease is currently not well understood, but it is generally regarded that the pressure of the endolymphatic fluid of the internal ear is pathologically increased leading to a condition called hydrops (swelling of the membraneous labyrinth including the cochlea of the internal ear due to too high pressure). The increased pressure may cause ruptures of the membranes in the labyrinth reducing the increased pressure and thus alleviating the symptoms of the acute attacks. The anatomy of the internal ear is described below.
In spite of the fact that Meniere's disease is relatively common and disabling there is no causal therapy for the disease. Currently all efforts have to be directed towards symptomatic treatment or to direct destructive treatment of the internal ear by surgical intervention or by administration of ototoxic drugs such as gentamycin into the ear. Thus, Meniere's disease is a significant clinical problem causing much suffering to patients, and consequently a causal therapy for the acute attacks as well as the symptoms during the remissions would be very desirable from a clinical point of view.
Tinnitus, the perception of sound in absence of acoustic stimulus, is a very common disorder amongst middle age and elderly people. As many as 10 percent of the middle age/elderly population may suffer from some degree of tinnitus. Most patients complaining of tinnitus however do not suffer from Meniere's disease, but have a local disorder in the organ of Corti which contains the hair cells. These cells transform mechanic energy into electrochemical energy for propagation of the hearing impulses to the brain. The pathophysiologic ethiology of tinnitus is poorly understood. Various causes of tinnitus may include acoustic trauma leading to permanent destruction e.g. of hair cells in the organ of Corti, microvasculopathies in the cochlea, toxic effects of drugs, and infections. Often tinnitus is associated with a hearing loss, which can be determined by audiometry. There are many variants of tinnitus some of which are caused by disorders in the tympanic membrane and external ear and which often can be successfully treated, but usually tinnitus derived from the inner ear is incurable or difficult to treat.
Hearing loss or hearing impairment, i.e. the inability to perceive the normal range of sounds audible to an individual with normal hearing, is also a very common disorder. Hearing loss may be greater at some frequencies than others, or all frequencies may be equally affected. The etiology of hearing loss is quite complex, and not fully elucidated. Causative factors may be physical damage to the outer or middle ear, acute or chronic acoustic trauma, ageing, damage to the inner ear or the auditory nerve. It is also not uncommon that hearing loss appears as a sequelae to other diseases or as an unwanted side effect of certain pharmaceuticals.
In the present description, examples and claims, the terms hearing loss and tinnitus are used in their widest meaning, as generally understood by a person skilled in the art.
Currently there are no clinically proven remedies for the treatment of tinnitus or hearing loss, and a drug that could be used to prevent, alleviate or eliminate these symptoms would thus be very desirable from a clinical point of view.
Anatomy and Physiology of the Ear
The ear is divided into three main parts; the external ear, the middle ear and the inner ear. The external ear consists of the auricle (pinna) and the ear canal which ends at the tympanic membrane. The middle ear consists of the tympanic membrane, the tympanic cavity, the auditory ossicles and the Eustachian tube. The inner ear, also called the labyrinth because of its complex structure, consists of sacs and tubules suspended in cavities of the petrous portion of the temporal bone. These structures contain a fluid called the endolymph, while the space between the membranous labyrinth and the bone is filled with the perilymph. The bony labyrinth consists of two parts; the vestibule which houses the saccule, the utricle, the semicircular canals, and the cochlea, a spirally coiled structure. The sense of balance is located in the vestibule while the sense of hearing is located in the cochlea.
The cochlea is a two and three quarters coiled cavity in the bone containing a membranous structure filled with fluid. The cochlear membraneous structure comprises three cavities; the scala vestibuli connected to the oval window and the middle ear ossicles; the scala tympani connected to the round window at the middle ear; and finally the scala media or the cochlear duct being part of the endolymphatic system. The scala vestibuli and scala tympani are parts of the perilymphatic system. The scala media contains the sound perceiving organ, the organ of Corti, a complex structure containing hair cells receiving the hydromechanical energy and converting it to electrochemical signals, supporting cells, a basilar membrane and a tectorial membrane as well as nerve fibres connecting the organ to the nearby situated spiral ganglion. From the spiral ganglion nerve fibres project to the brain for further processing of the auditory signals. The scala media also contains a highly vascularized structure called stria vascularis, and it is regarded that the endolymph of the cochlea is formed in this structure.
The sound reaching the tympanic membrane of the middle ear will cause it to vibrate and the energy is then passed on to the oval window of the inner ear through the ossicles. The energy from the oval window causes a pressure wave in the scala vestibuli to be conveyed through the tip of the cochlea through an opening into the scala tympani which is connected to the round window at the middle ear. This pressure wave in the perilymphatic fluid system causes through the basilar membrane the hair cells to vibrate against the tectorial membrane thus transforming mechanical energy into electrochemical energy. Finally most of the energy from the external sound is released from the cochlea into the middle ear through the round window membrane.
The endolymphatic system of the cochlea is connected through ductus reuniens to the endolymphatic system of the sacculus in the vestibular organ. The sacculus is further connected to the utriculus joined by three semicircular canals. The sacculus, utriculus and the semicircular canals have a physiologic function in detecting movements and position and thus relate to the sense of balance. Disorders in this part of the inner ear usually cause symptoms of vertigo often associated with nausea. Both the utriculus and the sacculus are connected through a small canal called the endolymphatic duct to the endolymphatic sac. The endolymphatic duct, a minuscule structure, has a very important function in that the endolymph is believed to be resorbed into the lymphatic and/or blood vessels in this structure.
Thus the endolymph is believed largely, if not totally, to be formed in the stria vascularis of the scala media of the cochlea and the wall of the utriculus. It then slowly flows from the cochlea into the sacculus and utriculus to finally end up in the endolymphatic duct and sac where it is resorbed. The endolymphatic duct is a tiny about 2 mm long narrow canal embedded in loose connective tissue in the corresponding bony canal. Lymphatics and blood vessels run through the loose connective tissue. The endolymphatic duct is lined by a single epithelial cell layer and water and solutes have to traverse this cell layer to enter the loose connective tissue. From here the water is resorbed into the lymphatic vessels or the veins because the intraluminal pressure is negative (estimated to −5 to −10 mmHg) compared to the atmospheric pressure (0 mmHg) in the connective tissue stroma and the endolymphatic duct. Thus it is likely that the driving force for the endolymph to leave the endolymphatic duct is largely the difference in hydrostatic pressure between endolymphatic duct and the lymphatic vessels and veins in the connective tissue stroma. The lymphatic vessels empty into the veins. Oncotic pressure gradients are unknown. It is presently regarded that, in Meniere's disease, the resorption of the fluid is impaired leading to increased pressure in the endolympahtic fluid both in the vestibule and the cochlea resulting in typical symptoms such as vertigo, nausea, hearing impairment and tinnitus.